ABSTRACT While much is known about the etiology of incident coronary heart disease (CHD) from genetic and experimental studies, far less is known about the causes of CHD recurrence, and new treatment strategies for secondary prevention have been slow to emerge. High-throughput affinity-based proteomics now allows for an evaluation of hundreds or even thousands of proteins in large populations, and recent studies suggest that this approach can lead to the discovery of novel proteins associated with various cardiovascular diseases. Moreover, the integration of genomic data and use of Mendelian randomization methods can help distinguish between protein biomarkers and causal factors for disease. The goals of this project are to use proteomics to improve our understanding of the etiology of recurrent CHD, and to identify proteins that are new causal factors and potential therapeutic targets for the secondary prevention of CHD. In the Heart and Vascular Health (HVH) Study, we propose to use a proteomics platform based on the proximity extension assay to measure 1,160 plasma proteins in an inception cohort of 1,575 survivors of an acute myocardial infarction (AMI), validate recurrent CHD events during up to 16 years of follow up, and evaluate longitudinal protein associations with recurrent CHD risk. The HVH Study has GWAS data and rich information on cardiovascular risk factors, comorbidities, and post-AMI interventions and medication use from electronic databases and medical records. Potential sources of bias in studies of disease recurrence will be minimized with the use of appropriate study designs and statistical approaches. Genomic data from the HVH Study and from larger external populations will be used to select strong genetic determinants for Mendelian randomization experiments, which will evaluate whether protein associations with recurrent CHD risk are likely to be causal. For the highest priority proteins that emerge from the discovery analyses, we will use inexpensive targeted immunoassays to validate proteins and to replicate associations in population-based cohorts and in studies of patients with recent acute coronary syndrome. Aim 1 of this project is to use proteomic and genomic data to identify, validate, and replicate casual protein associations with recurrent CHD among survivors of an incident AMI. Aim 2 is to use this approach to identify novel protein associations with secondary outcomes (heart failure, atrial fibrillation, and mortality). Because of the large number of events during follow up, we have excellent power to identify protein associations for both the primary aim (HR 1.19) and secondary aims (HR 1.16-1.29). This efficient approach can accelerate the discovery of new therapeutic targets for the secondary prevention of CHD, which are currently lacking.